Within the realm of chemistry the specific aims of this project are: 1) to develop new methodology for incorporating fluorine atoms into the carbohydrate moiety of nucleosides; 2) to devise synthetic routes to nucleotide analogs in which 0-3' or 0-5' are replaced by the CF2 group; 3) to synthesize analogs of nucleoside polyphosphates and oligonucleotides in which the anionic P-O- group is replaced by the P-CF3 group. The primary area of exploration with regard to fluoronucleosides will be a search for methods to incorporate a CF2 unit at C-2' of ribose in place of the CHOH group. Both direct modification at the nucleoside level as well as de novo fluorosugar syntheses will be pursued. Structural studies are planned to ascertain the influence of the CF2 and CF3 groups on nucleoside and nucleotide structure, from which increased understanding about the factors that contribute to the sugar-phosphate backbone conformation of polynucleotides may be gained. One objective of our research program is to create nucleoside analogs and molecular probes for studying the biochemistry of DNA replication. Where appropriate, the effect of some of these analogs (nucleoside 5'-triphosphates modified on either C-2', C-5', or phosphorous) on DNA synthesis will be examined.